Investigating Stem Cell Misspecification and Tumor Heterogeneity in Cutaneous Basal Cell Carcinoma Open Access

Patel, Kush (Spring 2025)

Permanent URL: https://etd.library.emory.edu/concern/etds/2j62s632j?locale=en

Published

The epidermal barrier consists of adherent, polarized epithelial cell layers that require continuous

replenishment by basal stem cells, whose proliferative nature is believed to contribute to skin

tumorigenesis. Our previous work in a cisplatin-treated mouse model demonstrated that IL-1β

secretion following NLRP3 inflammasome activation in dermal fibroblasts induces epidermal

hyperplasia and disrupts stem cell differentiation, resembling tumorigenic behaviors. In this study,

we investigated whether stem cell misspecification and inflammasome activation contribute to

cutaneous basal cell carcinoma (cBCC) tumorigenesis, the most common human cancer. Using an

established cBCC mouse model in which the Sonic Hedgehog pathway is constitutively activated,

we analyzed stem cell misspecification and inflammasome activation through

immunofluorescence and confocal microscopy. We observed no inflammasome activation in

cBCC tumors, suggesting this signaling pathway does not contribute to tumorigenesis. However,

we identified two distinct tumor subtypes: macrotumors, composed primarily of K14+ basal stem

cells, and microtumors, which contained K10/K14 dual-positive cells, reminiscent of stem cell

misspecification previously observed in our cisplatin-treated model. To further distinguish these

tumor types, we analyzed proliferation markers and found that macrotumors exhibited widespread

BrdU expression, indicating high levels of proliferation, whereas microtumors displayed

proliferation in small cell subpopulations, suggesting proliferative heterogeneity. Given these

differences in tumor architecture and proliferation, our future work will investigate the

mechanisms driving differential proliferation across tumor cell populations. Using a transgenic

cBCC mouse model, we will culture distinct tumor cell populations to assess the plasticity and

lineage potential of K14+ and K10/K14 dual-positive cells and perform spatial transcriptomics to

uncover molecular mechanisms underlying these distinctions. Identifying the molecular drivers of

tumor heterogeneity may reveal novel therapeutic targets for regulating tumor growth and

differentiation in cBCC.

Chapter I: Introductions .......................................................................................................1

Chapter II: Materials and Methods ....................................................................................15

Chapter III: Results ............................................................................................................21

Chapter IV: Discussion ......................................................................................................33

References ..........................................................................................................................42

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Keyword	stem cell tumorigenesis Hedgehog signaling basal cell carcinoma hair follicle epithelia keratin plasticity differentiation
Committee Chair / Thesis Advisor	Lindsey Seldin, Emory University
Committee Members	Victor Faundez, Emory University Anita Corbett, Emory University

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