Michael F. Clarke
· MD Karel H. and Avice N. Beekhuis Professor of Cancer BiologyVerifiedStanford University · Medical Oncology
Active 1983–2026
About
Michael F. Clarke, M.D., is the Karel H. and Avice N. Beekhuis Professor of Cancer Biology and Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. He is a board-certified oncologist with extensive training in molecular biology and stem cell biology. His laboratory focuses on two main areas of research: the control of self-renewal of normal stem cells and their malignant counterparts, and the identification and characterization of cancer stem cells. His work aims to understand how perturbations in self-renewal machinery contribute to human diseases and to develop more effective treatment therapies. Dr. Clarke's research has a history of innovative findings, including demonstrating that inappropriate expression of a normal gene can cause a tumor, identifying a dominant-negative splice variant of an oncogene, and discovering molecular regulators of stem cell self-renewal. His group was the first to identify a solid tumor stem cell in breast cancer and to demonstrate a molecular link between normal mammary stem cell self-renewal programs and breast cancer cells. Recently, his team described a molecular mechanism conferring radiation resistance in breast cancer stem cells. His laboratory also discovered that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism and that USP16, a protein that dampens Bmi-1 signals, causes stem cell defects in Down’s syndrome neural stem cells. His research extends to understanding the genetic mutations in cancer cells, using single-cell genomics to analyze tissue hierarchy in normal and malignant cells in various tumors. His work emphasizes targeting tumorigenic cancer stem cells to improve treatment outcomes. Additionally, his laboratory investigates how cancer stem cells self-renew and escape genetic constraints, with the goal of identifying pathways that can be targeted therapeutically to eliminate these cells.
Research topics
- Biology
- Genetics
- Computational biology
- Computer Science
- Artificial Intelligence
- Cell biology
- Data Mining
- Evolutionary biology
- Database
Selected publications
Cancer Research · 2026-04-03
articleAbstract Background: Radiotherapy (RT) is central to breast cancer (BC) management but limited by normal tissue toxicity. Conventional RT (CONV; ≤0.03 Gy/s) controls tumors but often causes skin inflammation, compromises treatment intensity and quality of life. Ultra-high dose-rate FLASH RT (>40 Gy/s) achieves comparable tumor control with markedly reduced tissue injury (“FLASH effect”), yet its mechanism of tumor control and sparing of normal tissue remains unclear. Ionizing radiation activates the cGAS-STING pathway through DNA damage, triggering proinflammatory cytokine production and tissue injury, yet has also been implicated with improvement in the antitumor immune response. Emerging data suggest that FLASH may attenuate or abrogate cGAS-STING signaling leading to reduced inflammation and tissue injury. This study investigated the role of cGAS signaling in mediating the differential effects of FLASH and CONV RT on normal tissue toxicity and tumor control using wild-type (WT) C57BL/6 and cGAS double knockout (cGAS -/- KO) mice. Methods: PYMT117 BC cells were orthotopically implanted into the third mammary fat pad of 6-8-week-old female WT and cGAS-/- mice. Once tumors reached ∼50 mm3, mice received a single 30 Gy dose of either FLASH or CONV RT targeted to the tumor site. Tumor growth and skin toxicity (graded 0-5) were measured every other day. Euthanasia was performed upon excessive tumor burden or skin injury. Data were analyzed by two-way ANOVA followed by Tukey’s post hoc test (p < 0.05). Results: Both FLASH and CONV RT significantly reduced tumor volume (p < 0.001), with complete regression by day 14. Tumor recurrence occurred around day 25 in all groups. In WT mice, both modalities produced comparable tumor control, with CONV showing a slight but non-significant trend toward smaller recurrent tumors and few complete responses but caused severe skin toxicity (score 5) requiring euthanasia by day 50-60. In contrast, FLASH treated mice showed equivalent tumor suppression markedly reducing skin toxicity (score ≤ 3 in 2/10 mice). Notably, the cGAS-/- mice exhibited minimal or no visible toxicity with either modality, except one CONV-treated mouse (score 2). Conclusion: FLASH RT significantly reduces normal tissue toxicity compared to CONV RT while maintaining equivalent tumor control: improved tumor control might be achievable through higher FLASH doses because of the improved therapeutic index over CONV RT. The minimal toxicity observed following FLASH RT, together with the absence of toxicity in cGAS-/- mice, also supports the possibility that FLASH may limit early inflammatory responses and tissue injury by suppression or abrogation of cGAS-STING activation. These findings support FLASH RT as a promising, less-toxic radiotherapeutic approach and highlights the potential of suppression of the cGAS-STING pathway to improve treatment outcomes in BC. Citation Format: Banita Verma, Adel Mutahar, Stavros Melemenidis, Rohit Verma, Lucy Whitemore, Suparna Dutt, Kathleen C. Horst, Edward Elliot Graves, Michael F. Clarke, Lingyin Li, Billy W. Loo, Frederick M. Dirbas. Impact of ultra-high dose rate (FLASH) versus conventional radiotherapy on tumor control in wild-type and cGAS-knockout mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5274.
Cancer Research · 2026-04-03
articleAbstract Background: Radiotherapy is central to breast cancer treatment but is limited by acute and cumulative skin toxicity, especially in large-field treatments and re-irradiation. Ultra-high-dose-rate FLASH radiotherapy (FLASH-RT, ≥ 40 Gy/s) may widen the therapeutic window by reducing normal-tissue injury without compromising tumor control. However, breast-directed and patient-derived models remain underexplored, including the effects of FLASH under repeated-irradiation conditions. Methods: We integrated an orthotopic triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model and hemithoracic normal-tissue models to compare FLASH-RT (180 Gy/s) with CONV-RT (0.03 Gy/s). TNBC-bearing NRG mice received single-fraction of 30Gy electron irradiation via a custom stereotactic jig enabling mammary-targeted or hemithoracic fields. A separate cohort of non-tumor-bearing NRG mice underwent left-chest re-irradiation to assess cumulative tolerance. Endpoints included tumor regression, recurrence, survival, and graded skin toxicity; ongoing analyses incorporate histopathology and single-cell/spatial transcriptomics to elucidate FLASH-mediated tissue responses and mechanisms of normal-tissue sparing. Results: FLASH-RT achieved equivalent tumor control to CONV-RT in TNBC-PDX models, with both modalities inducing complete regression by day 16 and maintaining clearance for two weeks before recurrence at day 32 post-RT. In contrast, normal-tissue responses diverged markedly: FLASH-RT significantly reduced acute skin toxicity (median score 0 vs. 5; p<0.0001), eliminated ulceration, and extended survival (120 vs. 90 days post-implantation) in tumor bearing mice. In non-tumor-bearing NRG mice, FLASH-RT also improved tolerance to cumulative thoracic irradiation; mice receiving a second 25Gy left-chest FLASH irradiation dose showed no clinical decline, whereas CONV-RT animals developed progressive toxicity requiring euthanasia within three months of re-irradiation. Multi-omics analyses are underway to define mechanisms of early tissue sparing and improved re-irradiation response. Conclusions: FLASH-RT maintains tumor-control efficacy equivalent to CONV-RT while significantly reducing skin toxicity in TNBC-PDX models and improving normal-tissue tolerance to re-irradiation in non-tumor-bearing NRG mice. These findings support FLASH-RT as a clinically promising strategy that may expand safe re-treatment options and broaden curative radiotherapy opportunities in breast cancer. Mechanistic studies are ongoing to elucidate the biological basis of early tissue sparing and guide translation into breast-conserving and post-mastectomy treatment settings. Citation Format: Adel Zaid I Mutahar, Banita Verma, Stavros Melemenidis, Suparna Dutt, Kerriann M. Casey, Zhen Qi, Angera Hsiao-Chi Kuo, Kathleen C. Horst, Edward Elliot Graves, Michael F. Clarke, Billy W. Loo, Frederick M. Dirbas. FLASH radiotherapy maintains tumor control and enables safe re-irradiation while preserving normal tissue in breast cancer PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5266.
Improved reconstruction of single-cell developmental potential with CytoTRACE 2
Nature Methods · 2025-10-27 · 45 citations
articleOpen accessWhile single-cell RNA sequencing has advanced our understanding of cell fate, identifying molecular hallmarks of potency-a cell's ability to differentiate into other cell types-remains a challenge. Here we introduce CytoTRACE 2, an interpretable deep learning framework for predicting absolute developmental potential from single-cell RNA sequencing data. Across diverse platforms and tissues, CytoTRACE 2 outperformed previous methods in predicting developmental hierarchies, enabling detailed mapping of single-cell differentiation landscapes and expanding insights into cell potency.
A molecular cell atlas of mouse lemur, an emerging model primate
Nature · 2025-07-30 · 8 citations
articleOpen accessAbstract Mouse lemurs are the smallest and fastest reproducing primates, as well as one of the most abundant, and they are emerging as a model organism for primate biology, behaviour, health and conservation. Although much has been learnt about their ecology and phylogeny in Madagascar and their physiology, little is known about their cellular and molecular biology. Here we used droplet-based and plate-based single-cell RNA sequencing to create Tabula Microcebus, a transcriptomic atlas of 226,000 cells from 27 mouse lemur organs opportunistically obtained from four donors clinically and histologically characterized. Using computational cell clustering, integration and expert cell annotation, we define and biologically organize more than 750 lemur molecular cell types and their full gene expression profiles. This includes cognates of most classical human cell types, including stem and progenitor cells, and differentiating cells along the developmental trajectories of spermatogenesis, haematopoiesis and other adult tissues. We also describe dozens of previously unidentified or sparsely characterized cell types. We globally compare expression profiles to define the molecular relationships of cell types across the body, and explore primate cell and gene expression evolution by comparing lemur transcriptomes to those of human, mouse and macaque. This reveals cell-type-specific patterns of primate specialization and many cell types and genes for which the mouse lemur provides a better human model than mouse 1 . The atlas provides a cellular and molecular foundation for studying this model primate and establishes a general approach for characterizing other emerging model organisms.
Cancer Research · 2025-04-21
articleAbstract Background: Triple-negative breast cancer (TNBC), defined by a lack of hormone receptors and lack of HER2 amplification, is the deadliest subtype of breast cancer. TNBC kills 1 in 3 patients and while promising new drugs based on PARP inhibition and anti-PD1 immunotherapy can extend survival in selected patients, 30-40% of patients relapse or fail therapy. Increasing evidence suggests that TNBC tumors harbor stem-like tumorigenic cancer cells with high plasticity, capable of replenishing cancer cell populations and linked to adverse outcomes. Unfortunately, the phenotypic diversity, microenvironmental contexture, and functional significance of these cells remain poorly understood and available marker genes are not specific, precluding rational drug development. Methods: We created a multimodal single-cell RNA-seq atlas of 80 TNBC patients, including clinical covariates such as BRCA1/2 mutations, race/ethnicity, and prior treatment status. We then defined differentiation-associated malignant cell states using a novel interpretable deep learning approach for determining single-cell potency. We subsequently interrogated geospatial features, including localized microenvironments of less differentiated malignant cells, and linked them to immune checkpoint inhibitor (ICI) response. Results: Our quantitative analysis shows that TNBC is enriched in cancer cells with high developmental potency as compared to other breast cancer subtypes, consistent with its aggressive phenotype. Critically, we observed a strong association between enrichment of high potency cells and resistance to ICI treatment across human and mouse bulk expression data, both within TNBC and across other cancer types, a finding that we experimentally validated in a murine model of TNBC. In scRNA-seq and spatial transcriptomics data, we defined striking relationships between less differentiated cancer cells and context-dependent T cell states indicative of strong immunosuppressive capability. In line with this, we found that knockout of genes associated with immature cancer cells promotes TNBC cell killing by T cells in a co-culture CRISPR screen. Ongoing experiments include perturbations of novel therapeutic targets emerging from this work, with the goal of improving immunotherapy responses and ultimately extending patient survival. Conclusion: We anticipate that our approach will expand our understanding of developmental landscapes in TNBC and lead to new opportunities for developing targeted drugs in this devastating disease. Citation Format: Rachel Gleyzer,Farnaz Khameneh,Zhen Qi,Wubing Zhang,Chloé B. Steen,Minji Kang,Maya Maalouf,Melanis Ghadimi,Makenna Lindsey,Sally Bobo,Thomas J. Lomis,Frederick M. Dirbas,Michael F. Clarke,Aaron M. Newman. Decoding developmental programs driving tumorigenesis and immunotherapy resistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 113.
Cancer Research · 2025-04-21
articleSenior authorAbstract Background: The development of chemoresistance in many cancer patients poses a significant clinical challenge, while the underlying causes for heterogeneous drug responses remain largely elusive. Increasing evidence suggests that tumors exhibit extensive heterogeneity and harbor cancer subpopulations in less differentiated states that are linked to treatment resistance. Therefore, dissecting immature cancer cell states pre-existing in tumors is essential for identifying biomarkers associated with chemoresistance and establishing targeted therapeutic strategies, particularly in breast cancer, where specific biomarkers are largely lacking. Methods: We utilized CytoTRACE, a robust computational framework for predicting the cellular differentiation status from single-cell RNA sequencing data, to unveil the immature cancer cell state and its associated markers in single-cell atlases of human breast cancer. The association between the identified immature cell state and patient survival was determined by inferring the proportions of epithelial cancer cells expressing the marker gene in bulk gene expression datasets. The MMTV-PyMT mouse breast cancer model was used to experimentally investigate the role of the immature cancer cell state in conferring chemoresistance. Single-cell profiling was conducted on tumor samples before and after treatment to examine the inherent characteristics of immature cancer cells and their response to drug pressure. The results obtained from mouse tumors were subsequently confirmed using human breast cancer models. Results and Conclusion: We revealed that BCL11B, a zinc finger transcription factor, defines a distinct immature cancer cell state in human breast cancer that displays basal cell features and demonstrates a heterogeneous expression pattern across breast tumors. Breast cancer patients with higher levels of BCL11B+ cancer cells face a significantly increased risk of relapse following chemotherapy. This pre-existing tumor subpopulation exhibits intrinsic fitness advantages and demonstrates a remarkable ability to evolve into a drug-resistant state through various BCL11B-dependent pre-existing and transcriptional adaptation mechanisms. Notably, TNF-α was pinpointed as a natural inhibitor of BCL11B, and treatment with TNF-α significantly increases chemotherapy efficacy by inducing the exit of the drug-resistant cell state. In conclusion, our findings identify BCL11B as a valuable biomarker for predicting chemotherapy resistance and suggest TNF-α combination treatment for breast cancer patients at high risk of developing chemoresistance. Citation Format: Zhen Qi,1 Gunsagar S. Gulati,2 Angera H. Kuo,1 Shaheen S. Sikandar,3 William Hai Dang Ho,1 Dalong Qian,1 Frederick M. Dirbas,1 Aaron M. Newman,1 Shang Cai,4 Michael F. Clarke1. BCL11B predetermines an immature drug-resistant cell state in breast cancer that is vulnerable to TNF-α treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1256.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-24 · 2 citations
preprintOpen accessABSTRACT Background. Colorectal carcinomas (CRCs) are seldom eradicated by cytotoxic chemotherapy. Cancer cells with stem-like functional properties, often referred to as “cancer stem cells” (CSCs), display preferential resistance to several anti-tumor agents used in cancer chemotherapy, but the molecular mechanisms underpinning their selective survival remain only partially understood. Methods. In this study, we used Transcription Factor Target Genes (TFTG) enrichment analysis to identify transcriptional regulators (activators or repressors) that undergo preferential activation by chemotherapy in CRC cells with a “bottom-of-the-crypt” phenotype (EPCAM + /CD44 + /CD166 + ; CSC-enriched) as compared to CRC cells with a “top-of-the-crypt” phenotype (EPCAM + /CD44 neg /CD166 neg ; CSC-depleted). The two cell populations were purified in parallel by fluorescence-activated cell sorting (FACS) from a patient-derived xenograft (PDX) line representative of a moderately differentiated human CRC, following in vivo chemotherapy with irinotecan (CPT-11). The transcriptional regulators identified as differentially activated were tested for differential expression in normal vs. cancer tissues, and in cell populations enriched in stem/progenitor cell-types as compared to differentiated lineages (goblet cells, enterocytes) in the mouse colon epithelium. Finally, the top candidate was tested for mechanistic contribution to drug-resistance by selective down-regulation using short-hairpin RNAs (shRNAs). Results. Our analysis identified E2F4 and TFDP1, two core components of the DREAM transcriptional repression complex, as transcriptional modulators preferentially activated by irinotecan in EPCAM + /CD44 + /CD166 + as compared to EPCAM + /CD44 neg /CD166 neg cancer cells. The expression levels of both genes ( E2F4 , TFDP1 ) were found up-regulated in CRCs as compared to human normal colon tissues, and in a sub-population of mouse colon epithelial cells enriched in stem/progenitor elements (Epcam + /Cd44 + /Cd66a low /Kit neg ) as compared to other sub-populations enriched in either goblet cells (Epcam + /Cd44 + /Cd66a low /Kit + ) or enterocytes (Epcam + /Cd44 neg /Cd66a high ). Most importantly, E2F4 down-regulation using shRNAs dramatically enhanced the sensitivity of human CRCs to in vivo treatment with irinotecan , across three independent PDX models. Conclusions. Our data identified E2F4 and the DREAM repressor complex as critical regulators of human CRC resistance to irinotecan , and as candidate targets for the development of chemo-sensitizing agents.
Mouse lemur cell atlas informs primate genes, physiology and disease
Nature · 2025-07-30 · 4 citations
articleOpen access, we performed large-scale single-cell RNA sequencing of 27 organs from mouse lemurs. We identified more than 750 molecular cell types, characterized their transcriptomic profiles and provided insight into primate evolution of cell types. Here we use the generated atlas to characterize mouse lemur genes, physiology, disease and mutations. We uncover thousands of previously unidentified lemur genes and hundreds of thousands of new splice junctions including over 85,000 primate splice junctions missing in mice. We systematically explore the lemur immune system by comparing global expression profiles of key immune genes in health and disease, and by mapping immune cell development, trafficking and activation. We characterize primate-specific and lemur-specific physiology and disease, including molecular features of the immune program, lemur adipocytes and metastatic endometrial cancer that resembles the human malignancy. We present expression patterns of more than 400 primate genes missing in mice, many with similar expression patterns to humans and some implicated in human disease. Finally, we provide an experimental framework for reverse genetic analysis by identifying naturally occurring nonsense mutations in three primate immune genes missing in mice and by analysing their transcriptional phenotypes. This work establishes a foundation for molecular and genetic analyses of mouse lemurs and prioritizes primate genes, isoforms, physiology and disease for future study.
An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome
Nature Communications · 2024-03-11 · 10 citations
articleOpen accessHormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.
Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer
Nature Communications · 2024-06-17 · 29 citations
articleOpen accessCancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we build a chronological molecular clock at single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in female mice. We find that the mammary aging process is asynchronous and progressive, initiated by an early senescence program, succeeded by an entropic late senescence program with elevated cancer associated pathways, vulnerable to cancer predisposition. The transition towards senescence program is governed by a stem cell factor Bcl11b, loss of which accelerates mammary ageing with enhanced DMBA-induced tumor formation. We have identified a drug TPCA-1 that can rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings establish a molecular portrait of progressive mammary cell aging and elucidate the transcriptional regulatory network bridging mammary aging and cancer predisposition, which has potential implications for the management of cancer prevalence in the aged.
Recent grants
NIH · $2.9M · 2016
NIH · $2.5M · 2015
NIH · $1.1M · 2001
NIH · $671k · 1993
NIH · $933k · 2009
Frequent coauthors
- 91 shared
Irving L. Weissman
Stanford University
- 73 shared
Dalong Qian
- 59 shared
Stephen R. Quake
Stanford University
- 53 shared
Qiang Tian
- 53 shared
In-Kyung Park
Ewha Womans University
- 52 shared
Leroy Hood
Institute for Systems Biology
- 50 shared
Linheng Li
- 50 shared
Kaijun Li
Lishui Central Hospital
Awards & honors
- American Association of Physicians
- American Society of Clinical Investigation
- Rackham Award, University of Michigan
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