Biology subjects

Mohlmann, E.

Publications and source records attributed to Mohlmann, E..

3 recordsLinked to original sources

bioRxiv2026

EGFR INHIBITION PROMOTES ENTEROENDOCRINE CELL DIFFERENTIATION CONTRIBUTING TO TREATMENT-ASSOCIATED DIARRHEA

Enteroendocrine cells (EECs) are specialized sensors of the gastrointestinal (GI) epithelium that regulate gut function and systemic metabolism through hormone secretion. The molecular pathways directing intestinal stem cell (ISC) differentiation into EECs are incompletely understood due, in part, to their rarity. We sought to identify novel regulators of human EEC differentiation using a high-throughput screen of FDA-approved drugs and human duodenal organoids. Two epidermal growth factor receptor inhibitors (EGFRi) commonly used in cancer therapy and known to cause GI side effects, erlotinib and lapatinib, emerged as strong inducers of EEC differentiation, dramatically increasing chromogranin A (CHGA) expression compared to controls, while maintaining ISC function and organoid growth. EGFRi-treated organoids revealed robust and broad upregulation of EEC hormones, including serotonin (5HT), motilin (MLN), and somatostatin (SST), among others. In agreement with these findings, analysis of a patient cohort with lung cancer revealed an association with erlotinib use and increased circulating levels of the above EEC hormones compared to matched controls. Supporting a direct effect of EGFRi on EEC differentiation, mice treated with erlotinib demonstrated increased EEC numbers and hormones and showed EGFRi-associated diarrhea (EAD), a limiting side effect of these medications. Mechanistically, EGFRi induced upregulation of interferon (IFN) signaling targets during early ISC-to-EEC differentiation. Consistent with this, inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) attenuated EGFRi-induced EEC differentiation. These findings provide important insight into EEC differentiation that could inform treatment strategies for EAD, metabolic diseases, and GI diseases. Brief SummaryInhibition of EGFR signaling promotes human ISC-to-EEC differentiation through activation of STAT1 signaling.

cell biology↗

bioRxiv2026

Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer

Activating mutations in PI3K are one of the most frequent mutations in breast cancer and are associated with worse patient outcomes in many breast cancer subtypes. Despite intense interest, cancer treatments that target the PI3K pathway have been only modestly effective due to intrinsic and acquired resistance mechanisms which reactivate PI3K signaling. Here, we characterize a feedback mechanism by which PI3K pathway inhibitors increase insulin receptor substrate 2 (IRS2) abundance and demonstrate the role of IRS2 in promoting resistance to these drugs. In PIK3CA mutant breast tumors and cell lines, there is a significant reduction in IRS2 mRNA and protein abundance which is reversed by PI3K pathway inhibition and mediated by the transcription factor FOXO3. PIK3CA mutations do not alter IRS1 expression. IRS2 confers resistance to PI3K pathway inhibition by sustaining PI3K signaling in PIK3CA mutant, but not wild-type breast cancer cells. Increased IRS2 abundance also correlates with PI3K pathway inhibitor resistance across PI3K mutant cancer cell lines from a variety of tissues. The clinical relevance of these findings is highlighted by the frequency of PI3K mutations in cancer and the identification of a new target to address the challenges associated with prior efforts to block the reactivation of PI3K signaling during PI3K inhibition.

cancer biology↗

bioRxiv2023

Craniofacial diversity across Danionins and the effects of TH status on craniofacial morphology of two Danio species

The model zebrafish (Danio rerio) belongs to the Danioninae subfamily with a range of informative phenotypes. However, the craniofacial diversity across the subfamily is not fully described. To better understand craniofacial phenotypes across Danioninae we used microCT and 3D geometric morphometrics to capture skull shapes from nine species. The Danio species examined showed largely similar skull shapes, although D. aesculapii, the sister species to D. rerio showed a unique morphology. Two non-Danio species examined, Chela dadiburjori and Devario aequipinnatus showed distinct skull morphologies unique from those of other species examined. Thyroid hormone regulates skeletal development and remodeling, and we asked if changes in developmental thyroid hormone metabolism could underlie some of the craniofacial diversity across Danioninae. We reared two Danio species under altered thyroid profiles, finding that hypothyroid individuals from both species showed corresponding morphological shifts in skull shape. Hypothyroid Danios showed skull morphologies closer to that of Chela and unlike any of the examined wild-type Danio species. We provide an examination of the evolved craniofacial diversity across Danioninae, and demonstrate that alterations to thyroid hormone have the capacity to create unique skull phenotypes.

evolutionary biology↗