Biology subjects

Chodosh, L. A.

Publications and source records attributed to Chodosh, L. A..

5 recordsLinked to original sources

bioRxiv2026

Loss of Ferroptosis-suppressors Accelerates Breast Cancer Recurrence by Promoting Dormancy Exit

Breast cancer mortality is principally due to recurrent metastatic disease that may commonly emerge from a state of dormant minimal residual disease following definitive treatment of a primary tumor. Our genomic analysis of paired primary and metastatic breast cancers arising in the same patients resulted in the identification of the ferroptosis pathway as being preferentially mutated in metastases. An in vivo CRISPR-Cas9 screen of known ferroptosis regulators in mice identified guides targeting PNPLA2, GOT1, and GPX4 as being selected for in late dormancy and recurrence, which was surprising given the ferroptosis-suppressing functions ascribed to these proteins. However, recurrence-free survival assays in mice confirmed that deletion of PNPLA2, GOT1, or GPX4 accelerated tumor recurrence in mice and provided further evidence that this acceleration was attributable to an increased probability that dormant tumor cells deleted for these genes would reenter the cell cycle. Using a model of therapy-associated breast cancer dormancy, we also found that dormant cancer cells were markedly resistant to ferroptosis-inducing stimuli, including erastin and RSL3. Moreover, dormant tumor cells lacking PNPLA2, GOT1, or GPX4 displayed enhanced ferroptosis resistance compared to wildtype cells. Probing this ferroptosis-resistant state revealed that the ratio of reduced to oxidized glutathione was elevated in dormant cells. Moreover, deletion of PNPLA2, GOT1, or GPX4 further increased this ratio in dormant cells, suggesting that an increased ratio of reduced to oxidized glutathione may contribute to ferroptosis resistance in dormant tumor cells, especially those lacking these genes, potentially by rendering them more capable of handling lipid oxidative stress. Consistent with our findings in mice, analysis of human breast cancer patient data revealed that patients with copy number loss of PNPLA2, GOT1, or GPX4 exhibited worse recurrence-free and overall survival. Together, our study implicates three genes in the process of recurrence from dormant tumor cells and identifies a unique metabolic feature of the dormant tumor cell state. The surprising resistance to ferroptosis inducers exhibited by dormant tumor cells, as well as counterintuitive effects of deleting ferroptosis-suppressing genes on tumor recurrence following dormancy, raise questions regarding the utility of targeting ferroptosis in cancer that merit further study.

cancer biology↗

bioRxiv2025

Residual Breast Cancer Cells Co-opt SOX5-driven Endochondral Ossification to Maintain Dormancy

Recurrent breast cancer accounts for most disease-associated mortality and can develop decades after primary tumor therapy. Recurrences arise from residual tumor cells (RTCs) that can evade therapy in a dormant state, however the mechanisms are poorly understood. CRISPR-Cas9 screening identified the transcription factors SOX5/6 as functional regulators of tumor recurrence. Loss of SOX5 accelerated recurrence and promoted escape from dormancy. Remarkably, SOX5 drove dormant RTCs to adopt a cartilage-dependent bone development program, termed endochondral ossification, that was confirmed by [18F]NaF-PET imaging and reversed in recurrent tumors escaping dormancy. In patients, osteochondrogenic gene expression in primary breast cancers or residual disease post-neoadjuvant therapy predicted improved recurrence-free survival. These findings suggest that SOX5-dependent mesodermal transdifferentiation constitutes an adaptive mechanism that prevents recurrence by reinforcing tumor cell dormancy.

cancer biology↗

bioRxiv2024

Cancer-Associated Hypercalcemia Signals Through the Hindbrain to cause Anorexia

Hypercalcemia, caused by tumor secretion of parathyroid hormone-related protein (PTHrP), is associated with anorexia and weight loss. We demonstrate that overexpression of PTHrP by tumor cells in a transgenic model of breast cancer causes anorexia and rapid weight loss. These changes are accompanied by activation of neurons in the area postrema (AP), the nucleus tractus solitarius (NTS) and the parabrachial nucleus (PBN), a hindbrain circuit regulating food intake. Blocking hypercalcemia prevents anorexia and activation of these brain centers in tumor bearing mice, whereas injecting calcium activates the same circuit in wild-type mice. Neurons in the AP express the calcium-sensing receptor (CaSR) and the same AP/NTS/PBN circuit is stimulated by treating WT mice with cinacalcet, an allosteric activator of the CaSR. Finally, treating diet-induced obese mice with cinacalcet reduces food intake and causes weight loss. These results suggest that CaSR-expressing neurons in the AP might be a pharmacologic target for obesity.

cancer biology↗

bioRxiv2023

B3GALT6 Promotes Dormant Breast Cancer Cell Survival and Recurrence by Enabling Heparan Sulfate-Mediated FGF Signaling

Breast cancer mortality results primarily from incurable recurrent tumors seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling dormant RTC survival is therefore essential for improving patient outcomes. We derived a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant chemotherapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identified the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 covalently attaches glycosaminoglycans (GAGs) to proteins to generate proteoglycans and its germline loss-of-function causes skeletal dysplasias. We determined that B3GALT6-mediated biosynthesis of the GAG heparan sulfate predicts poor patient outcomes, promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings identify a role for B3GALT6 in cancer and suggest targeting FGF signaling as a novel approach to preventing recurrence by eradicating dormant RTCs.

cancer biology↗

bioRxiv2021

PTHrP Induces STAT5 Activation, Secretory Differentiation and Mammary Tumor Progression

BackgroundParathyroid hormone-related protein (PTHrP) is required for embryonic breast development and has important functions during lactation, when it is produced by alveolar epithelial cells and secreted into the maternal circulation to mobilize skeletal calcium used for milk production. PTHrP is also produced by breast cancers and GWAS studies suggest that it influences breast cancer risk. However, the exact functions of PTHrP in breast cancer biology remain unsettled. MethodsWe developed a tetracyline-regulated, MMTV (mouse mammary tumor virus)-driven model of PTHrP overexpression in mammary epithelial cells (Tet-PTHrP mice) and bred these mice with the MMTV-PyMT (polyoma middle tumor-antigen) breast cancer model to analyze the impact of PTHrP overexpression on normal mammary gland biology and in breast cancer progression. ResultsOverexpression of PTHrP in luminal epithelial cells caused alveolar hyperplasia and secretory differentiation of the mammary epithelium with milk production. This was accompanied by activation of Stat5 and increased expression of E74-like factor-5 (Elf5). In MMTV-PyMT mice, overexpression of PTHrP (Tet-PTHrP;PyMT mice) shortened tumor latency and accelerated tumor growth, ultimately reducing overall survival. Tumors overproducing PTHrP also displayed increased expression of nuclear pSTAT5 and Elf5, increased expression of markers of secretory differentiation and milk constituents, and histologically resembled secretory carcinomas of the breast. Overexpression of PTHrP within cells isolated from tumors, but not PTHrP exogenously added to cell culture media, led to activation of STAT5 and milk protein gene expression. In addition, neither ablating the Type 1 PTH/PTHrP receptor (PTH1R) in epithelial cells or treating Tet-PTHrP;PyMT mice with an anti-PTH1R antibody prevented secretory differentiation or altered tumor latency. These data suggest that PTHrP acts in a cell-autonomous, intracrine manner. Finally, expression of PTHrP in human breast cancers is associated with expression of genes involved in milk production and STAT5 signaling. ConclusionsOur study suggests that PTHrP promotes pathways leading to secretory differentiation and proliferation in both normal mammary epithelial cells and in breast tumor cells.

cancer biology↗