Lung cancer is thought to develop in a stepwise fashion giving us the opportunity to intervene before it becomes invasive. A novel approach to cure patients of lung cancer is therefore to develop a targeted chemoprevention strategy to prevent the formation of lung premalignant lesions in the first place. My lab studies airway epithelial stem cells (AESCs) and the signaling pathways involved in their repair and regeneration after injury. Our studies led us to the conclusion that premalignancy represents a state of excessive self-renewal of AESCs with a block in differentiation and we identified several mechanisms involved in stepwise progression to lung cancer. One such mechanism involves proliferation of AESCs via the Wnt-?-catenin pathway and in particular we found that only one of the differential phosphorylation sites, the tyrosine Y489 residue of the ?-catenin protein, allowed nuclear localization of ?-catenin with concomitant TCF/LEF activation for proliferation. This phosphorylation of ?-catenin at Y489 is not present in normal airway AESCs but persists in premalignant lesions and lung cancer. We have developed human and mouse in vitro models of premalignancy in the proximal and distal airway epithelium by driving Wnt/?-catenin signaling. These models include the air-liquid interface model of proximal airway stem cell proliferation and differentiation (Aros et al, 2020) and a 3D lung organoid co-culture model with type I and type II alveolar epithelial cells. We are currently infecting our lung premalignancy models with SARS-CoV-2, in collaboration with Dr. Arumugaswami at UCLA to assess how viral infection alters this aberrant response to injury. Our hypothesis is that SARS-CoV-2 infection in the setting of premalignancy with excessive proliferation of AESCs will result in persistent Wnt/?-catenin signaling which will prevent the resolution of premalignant lesions and allow additional mutations to develop to drive invasive carcinoma. Our goal is to understand the effects of SARS-CoV-2 on Wnt/?-catenin signaling and especially p-?-cateninY489 in premalignant lesions using the following approaches:
Specific Aim : To understand the role of SARS-CoV-2 on p-?-cateninY489 in proliferation of AESCs in premalignant lesions. We hypothesize that p-?-cateninY489 is induced by SARS-CoV-2 for repair after infection and prevents resolution of existing premalignant lesions.
Specific Aim 1 a: We will identify how frequently SARS-CoV-2 infection drives Wnt/?-catenin signaling and leads to the p-?-cateninY489 in AESCs in proximal and distal airway models.
Specific Aim 1 b: We have identified a compound that prevents p-?-cateninY489 in AESCs (Aros et al, 2020) and will test the effects of this compound on SARS-CoV-2 infected proximal and distal airway premalignancy models.
Specific Aim 1 c: We will use transgenic mouse models with loss of ?-catenin in the AESCs of the proximal airway and examine the effects on repair of the airway after SARS-CoV-2 infection.
We have found that lung stem cells can drive precancerous lesions if they respond abnormally to lung injury and divide in an uncontrolled manner. We want to test whether COVID-19 drives the same abnormal response to lung injury that could patients at increased risk of lung cancer. We will test this with 3D models of the human lung that we have developed in the lab.
|Wilkinson, Dan C; Mellody, Michael; Meneses, Luisa K et al. (2018) Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling. Curr Protoc Stem Cell Biol 46:e56|