About

Dr. John Wysolmerski is an endocrinologist involved in patient care, medical education, and medical research. He is a Professor of Medicine and serves as Section Chief of Endocrinology and Metabolism. His outpatient clinical practice centers on disorders of mineral and bone metabolism, including osteoporosis, osteomalacia, hyperparathyroidism, hypoparathyroidism, osteogenesis imperfecta, hypercalcemia, hypocalcemia, and disorders of phosphate metabolism. His research focuses on the biological functions of parathyroid hormone-related protein and the calcium-sensing receptor in the breast, as well as the regulation of calcium and bone metabolism during lactation and in breast cancer.

Research topics

• Medicine
• Internal medicine
• Biology
• Endocrinology
• Oncology
• Chemistry
• Cancer research
• Intensive care medicine
• Cell biology
• Biochemistry

Selected publications

• Clinical and prognostic significance of parathyroid hormone-related protein in breast cancer: a systematic review and meta-analyses of observational studies in women

  Endocrine Related Cancer · 2026-02-16

  articleOpen accessSenior author

  Parathyroid hormone-related protein (PTHrP) is produced by normal breast epithelial cells and is a cause of hypercalcemia in breast and other cancers. However, there are conflicting data regarding its role(s) in breast cancer biology. This study aimed to clarify PTHrP's potential function(s) in breast cancer by systematically examining its association with tumor characteristics, patient outcomes and hypercalcemia in women. We designed a predetermined strategy based on PRISMA 2020 guidelines. Seven databases were interrogated to identify studies of women with breast cancer reporting associations between tumor or circulating PTHrP levels and prognostic factors, calcium levels, relapse and survival. The ROBINS-E tool was used to examine the risk of bias. Quantitative syntheses of outcomes were performed by drawing forest plots of individual studies and pooling estimates. Forty-five studies met our eligibility criteria. We found that PTHrP is likely associated with positive progesterone receptor status, the presence of microcalcifications and lymph node invasion, but not with tumor type or grade. Most studies interrogating the association between PTHrP expression and breast cancer prognosis or hypercalcemia were at a very high risk of bias. Despite this, our results suggest associations between PTHrP and patient survival, the presence of bone metastases and the diagnosis of hypercalcemia of malignancy. These meta-analyses underscore the need for robust multivariate analyses in women to rigorously re-evaluate the role of PTHrP in breast cancer. This is important since the gene coding for PTHrP (PTHLH) has been consistently identified as a breast cancer susceptibility locus.

  PublisherDOI

• Development of a floxed Gabbr2 gene allows for widespread conditional disruption of GABBR2 and recapitulates the phenotype of germline Gabbr2 knockout mice

  PLoS ONE · 2025-12-15

  articleOpen accessSenior authorCorresponding

  GABBR1 and GABBR2 are widely expressed in the brain and genetic inhibition of their function leads to neurologic dysfunction and premature death in mice. Given that GABBR1 and GABBR2 heterodimerize to form a functional receptor, global knockout of GABBR1 or GABBR2 results in a similar phenotype, characterized by spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory and premature death. Both GABBR1 and GABBR2 are expressed in a variety of tissues outside the nervous system and GABA-B receptors have been shown to heterodimerize with other class C GPCRs. However, the neurologic consequences of global GABBR1 or GABBR2 knockout mice have made it difficult to study the effects of loss of GABBR function in other organs. While a conditional knockout for GABBR1 is available, the Gabbr2 gene had not been "floxed". Therefore, we used CRISPR to insert loxP sites into the Gabbr2 locus in mice. These mice are normal at baseline but when bred with mice expressing Cre-recombinase under the control of the ubiquitously expressed Actin gene promoter, Gabbr2lox/lox mice recapitulate the phenotype of global GABBR2 knockout mice demonstrating alterations throughout the brain, including the cortex, hippocampus and cerebellum. We document abnormal neurological function, increased neuronal cell death, changes in neuronal architecture, and premature death. These mice should be useful tools to study cell type-specific loss of GABBR2 function in the brain and other organs.

  PublisherDOI

• Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer

  Breast Cancer Research · 2025-05-19 · 1 citations

  articleOpen accessSenior author

  Approximately 20% of breast cancers overexpress ErbB2/HER2/Neu, a receptor tyrosine kinase. Our previous studies demonstrated that HER2 interacts with the calcium pump, PMCA2, and the scaffolding molecules, NHERF1 and Ezrin to stabilize HER2/HSP90 interactions and contribute to the retention of active HER2 at the plasma membrane. In the normal mammary epithelium where apical/basal polarity is tightly regulated by junctional proteins, HER2 is expressed at low levels in the basolateral membrane and interacts with the LAP family member, Erbin, whereas PMCA2, NHERF1, and Ezrin localize to the apical membrane. Here, we show that loss of apical membrane polarity in hyperplastic lesions of MMTV-Neu mammary glands or in human DCIS leads to intermixing of these molecules and allows Erbin to interact with NHERF1, Ezrin and HER2 initially within the basolateral membrane and then more diffusely throughout the plasma membrane. In SKBR3 cells, Erbin interacts with NHERF1, Ezrin and HER2 in actin-rich membrane protrusions that we have previously described to be sites of active HER2 signaling. Knockdown of Erbin in these cells reduced HER2 signaling by disrupting the formation of a HER2/NHERF1/Ezrin/HSP90 protein complex in the membrane protrusions. Furthermore, inhibition of Ezrin or knock-down of NHERF1 expression disrupted the ability of Erbin to interact with HER2. Taken together, our data suggest that Erbin supports HER2 stability, HER2 membrane retention and HER2 transforming ability by interacting with Ezrin and NHERF1 to maintain a multi-protein signaling complex necessary for HER2-mediated transformation.

  PublisherOA PDFDOI

• Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-06

  preprintOpen access

  High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

  PublisherOA PDFDOI

• MON-779 Mild Primary Hyperparathyroidism Masquerading as Severely Overactive Parathyroid Function Behind PTH Assay Abnormalities

  Journal of the Endocrine Society · 2025-10-01

  articleOpen accessSenior author

  Abstract Disclosure: R.S. MacLeod: None. A. Ramirez: None. J.J. Wysolmerski: None. Introduction: Patients with primary hyperparathyroidism (PHPT) can exhibit hypercalcemia, kidney stones, and osteoporosis. Biochemical evidence or clinical signs of PHPT should be established before proceeding with further evaluation such as imaging modalities. Case: A 69-year-old woman with history of high-grade serous carcinoma of the ovary with extensive spread to the omentum, peritoneum, and bowel with tumor debulking surgery followed by multiple courses of chemotherapy on different protocols presents to endocrine surgery for new finding of suspected primary hyperparathyroidism. Chart review of her calcium values revealed in the 3 years following her surgery, she had intermittent hypercalcemia with a maximum total calcium (Ca) measurement of 11.0 (8.8-10.2) mg/dL. In the month prior to her endocrine surgery referral, she was noted to have elevated Ca to 10.5 mg/dL with first PTH measurement of 2006 (15-65) pg/mL on the Yale intact PTH assay. Repeat labs and further workup showed PTH of 1999 pg/mL, iCa of 5.47 mg/dL, magnesium 1.9 (1.7-2.4) mg/dL, 24-hour urine calcium of 123 (100-300) mg, and vitamin D25-hydroxy of 30 (20-50) ng/mL. A 4D CT scan of the neck showed suspicious parathyroid adenomas measuring 6 and 9mm. Bone mineral density evaluation of the axial and appendicular skeleton with DXA showed normal bone density of the lumbar spine and total hip and osteopenia of the femoral neck and distal radius. She was taken to surgery and had 3.5 parathyroid glands removed plus thymectomy yet her intraoperative PTH levels did not decline. Pathology revealed parathyroid hyperplasia with glands 324 mg/1.9 cm, 76 mg/0.9cm, and 59 mg/1 cm and no ectopic parathyroid tissue identified in the thymus. She was re-admitted 3 days later with symptoms of hypocalcemia with Ca of 7.0 mg/dL, iCa of 3.75 mg/dL, phosphorous of 5.7 (2.2-4.5) mg/dL, and PTH of 1984 pg/mL despite her symptoms and labs suggesting hypoparathyroidism. She was treated with calcium supplementation and calcitriol, and her symptoms improved. She had a clear mismatch in her immunoreactive PTH levels and serum calcium. Staining of her archived ovarian tumor samples was negative for PTH immunoreactivity. Single gene analysis of her PTH gene showed no abnormalities, and hypoparathyroid and hyperparathyroid genetic screens were negative for pathogenic variants, mutations, or variants of unknown significance. Simultaneous labs sent to Yale and Quest Diagnostics facilities revealed the following: Yale PTH 2112 pg/mL, Yale Ca 9.4 mg/dL, Quest intact PTH 47 (16-77) pg/mL, Quest Ca 9.4 (8.6-10.4) mg/dL. This indicated that she has a circulating factor that interferes with the Yale PTH immunoassay. Conclusion: Highly abnormal PTH values associated with relatively minor signs of PHPT should raise suspicion for immunoactivity mismatch and possible mutation or assay abnormality. Presentation: Monday, July 14, 2025

  PublisherOA PDFDOI

• Erbin interacts with NHERF1 and Ezrin to stabilize a membrane ErbB2 signaling complex in HER2-positive breast cancer

  Research Square · 2025-04-01

  preprintOpen accessSenior author
  PublisherDOI

• Development of a floxed <i>Gabbr2</i> gene allows for widespread conditional disruption of GABBR2 and recapitulates the phenotype of germline Gabbr2 knockout mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-23

  preprintOpen accessSenior author

  ABSTRACT GABBR1 and GABBR2 are widely expressed in the brain and genetic inhibition of their function leads to widespread neurologic dysfunction and premature death in mice. Given that GABBR1 and GABBR2 heterodimerize to form a functional receptor, global knockout of GABBR1 or GABBR2 results in a similar phenotype, characterized by spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory and premature death. It is now known that both GABBR1 and GABBR2 are expressed in a variety of tissues outside the nervous system and that GABA-B receptors can heterodimerize with other class C GPCRs, including the extracellular calcium-sensing receptor (CaSR). Studies in vitro have demonstrated that interactions with GABBR1 and GABBR2 can alter CaSR signaling in human embryonic kidney cells and breast cancer cells. The neurologic consequences of global loss of function of GABBR1 or GABBR2 has made it difficult to study the effects of loss of GABBR function in other organs. While a conditional knockout for GABBR1 is available, the GABBR2 gene had not been “floxed”. We have used CRISPR to insert loxP sites into the GABBR2 locus in mice. These mice are normal at baseline but when bred with mice expressing Cre-recombinase under the control of the ubiquitously expressed Actin gene promoter, they recapitulate the phenotype of global GABBR2 knockout mice. Phenotypic changes through the brain, including the cortex, hippocampus and cerebellum. Evidence of abnormal neuronal function, increase cell death, and changes in neuronal architecture are seen throughout the brain of CRISPR knockout mice. These mice should be useful tools to study cell type-specific loss of GABBR2 function in the brain and other organs.

  PublisherOA PDFDOI

• Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-15

  preprintOpen access

  Abstract Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 -knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested Hepatocyte nuclear factor 4-alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9 , a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

  PublisherOA PDFDOI

• Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

  eLife · 2024-06-04 · 7 citations

  articleOpen access

  Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9 , a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

  PublisherOA PDFDOI

• Reviewer #2 (Public Review): Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

  2024-06-04

  peer-reviewOpen access

  Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2-knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested Hepatocyte nuclear factor 4-alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

  PublisherDOI

Recent grants

• NIH Grant R01DK077565

  NIH · $1.3M · 2012

• NIH Grant R01CA094175

  NIH · $1.4M · 2007

• Diabetes Mellitus and Disorders of Metabolism

  NIH · $11.7M · 1975–2029

• NIH Grant R01DK055501

  NIH · $4.4M · 2015

• PTHrP and Cancer Cachexia

  NIH · $405k · 2019–2021

Frequent coauthors

• Pamela Dann

  Yale University

  51 shared

• Joshua VanHouten

  42 shared

• Jaekwang Jeong

  Yale University

  27 shared

• Andrew F. Stewart

  Icahn School of Medicine at Mount Sinai

  21 shared

• Wonnam Kim

  Pusan National University

  20 shared

• Wenhan Chang

  University of California, San Francisco

  20 shared

• Karl Insogna

  Yale University

  19 shared

• Farzin M. Takyar

  Research Institute for Endocrine Sciences

  16 shared