Fine-tuning of Epithelial EGFR signals Supports Coordinated Mammary Gland Development

Published on Sep 10, 2020in bioRxiv
· DOI :10.1101/2020.09.10.291872
A. Samocha1
Estimated H-index: 1
(UCSF: University of California, San Francisco),
H. Doh + 12 AuthorsJeroen P. Roose (University of California, Berkeley)
Sources
Abstract
Summary During puberty, robust morphogenesis occurs in the mammary gland; stem- and progenitor-cells develop into mature basal- and luminal-cells to form the ductal tree. The receptor signals that govern this process in mammary epithelial cells (MECs) are incompletely understood. The EGFR has been implicated and here we focused on EGFR’s downstream pathway component Rasgrp1. We find that Rasgrp1 dampens EGF-triggered signals in MECs. Biochemically and in vitro, Rasgrp1 perturbation results in increased EGFR-Ras-PI3K-AKT and mTORC1-S6 kinase signals, increased EGF-induced proliferation, and aberrant branching-capacity in 3D cultures. However, in vivo, Rasgrp1 perturbation results in delayed ductal tree maturation with shortened branches and reduced cellularity. Rasgrp1-deficient MEC organoids revealed lower frequencies of basal cells, the compartment that incorporates stem cells. Molecularly, EGF effectively counteracts Wnt signal-driven stem cell gene signature in organoids. Collectively, these studies demonstrate the need for fine-tuning of EGFR signals to properly instruct mammary epithelium during puberty.
References79
Newest
#1Katharina Lueck (UCL Institute of Ophthalmology)H-Index: 5
#2Amanda-Jayne F. Carr (UCL Institute of Ophthalmology)H-Index: 16
Last. Stephen E. Moss (UCL Institute of Ophthalmology)H-Index: 53
view all 5 authors...
Wnt signalling mediates complex cell-cellinteractions during development and proliferation. Annexin A8 (AnxA8), a calcium-dependent phospholipid-binding protein, and canonical Wnt signalling mechanisms have both been implicated in retinal pigment epithelial (RPE) cell differentiation. The aim here was to examine the possibility of cross-talk between AnxA8 and Wnt signalling, as both are down-regulated upon fenretinide (FR)-mediated RPE transdifferentiation. AnxA8 suppression in RPE cells via siR...
3 CitationsSource
#1A. Samocha (UCSF: University of California, San Francisco)H-Index: 1
#1Alexandr Samocha (UCSF: University of California, San Francisco)H-Index: 1
Last. Jeroen P. Roose (UCSF: University of California, San Francisco)H-Index: 32
view all 4 authors...
Fluidity in cell fate or heterogeneity in cell identity is an interesting cell biological phenomenon, which at the same time poses a significant obstacle for cancer therapy. The mammary gland seems a relatively straightforward organ with stromal cells and basal- and luminal- epithelial cell types. In reality, the epithelial cell fates are much more complex and heterogeneous, which is the topic of this review. Part of the complexity comes from the dynamic nature of this organ: the primitive epith...
1 CitationsSource
#2Caroline Bonnans (French Institute of Health and Medical Research)H-Index: 20
Last. Philippe DepeilleH-Index: 12
view all 17 authors...
Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncover that the EGFR-pathway component RasGRP1 acts as CRC tum...
3 CitationsSource
#1Quy H. Nguyen (UCI: University of California, Irvine)H-Index: 7
#2Nicholas Pervolarakis (UCI: University of California, Irvine)H-Index: 7
Last. Kai Kessenbrock (UCI: University of California, Irvine)H-Index: 22
view all 17 authors...
Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we use single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven ...
99 CitationsSource
#1Aline Wuidart (ULB: Université libre de Bruxelles)H-Index: 5
#2Alejandro Sifrim (Katholieke Universiteit Leuven)H-Index: 19
Last. Cédric Blanpain (ULB: Université libre de Bruxelles)H-Index: 82
view all 12 authors...
The mammary gland is composed of basal cells and luminal cells. It is generally believed that the mammary gland arises from embryonic multipotent progenitors, but it remains unclear when lineage restriction occurs and what mechanisms are responsible for the switch from multipotency to unipotency during its morphogenesis. Here, we perform multicolour lineage tracing and assess the fate of single progenitors, and demonstrate the existence of a developmental switch from multipotency to unipotency d...
75 CitationsSource
#1Norman Sachs (KNAW: Royal Netherlands Academy of Arts and Sciences)H-Index: 24
#2Joep de Ligt (UU: Utrecht University)H-Index: 30
Last. Hans Clevers (KNAW: Royal Netherlands Academy of Arts and Sciences)H-Index: 205
view all 31 authors...
Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variation...
459 CitationsSource
#1Lindsey Seldin (Vandy: Vanderbilt University)H-Index: 6
#2Armelle Le Guelte (Vandy: Vanderbilt University)H-Index: 10
Last. Ian G. Macara (Vandy: Vanderbilt University)H-Index: 85
view all 3 authors...
Many epithelial tissues rely on multipotent stem cells for the proper development and maintenance of their diverse cell lineages. Nevertheless, the identification of multipotent stem cell populations within the mammary gland has been a point of contention over the past decade. In this review, we provide a critical overview of the various lineage-tracing studies performed to address this issue and conclude that although multipotent stem cells exist in the embryonic mammary placode, the postnatal ...
14 CitationsSource
#1Bhupinder Pal (University of Melbourne)H-Index: 21
#2Yunshun Chen (University of Melbourne)H-Index: 8
Last. Jane E. Visvader (University of Melbourne)H-Index: 77
view all 14 authors...
The mammary epithelium comprises two primary cellular lineages, but the degree of heterogeneity within these compartments and their lineage relationships during development remain an open question. Here we report single-cell RNA profiling of mouse mammary epithelial cells spanning four developmental stages in the post-natal gland. Notably, the epithelium undergoes a large-scale shift in gene expression from a relatively homogeneous basal-like program in pre-puberty to distinct lineage-restricted...
91 CitationsSource
#1Yvonne Vercoulen (UCSF: University of California, San Francisco)H-Index: 9
#2Yasushi Kondo (University of California, Berkeley)H-Index: 11
Last. Jeroen P. Roose (UCSF: University of California, San Francisco)H-Index: 32
view all 9 authors...
Complex chain reactions between many kinds of molecules regulate every process in the body. For example, the signaling molecule Ras helps the cell to grow and divide. However, abnormally high levels of Ras signals can cause cancer. Ras is activated by proteins called exchange factors. One of the families of Ras exchange factors – RasGRP – plays important roles in immune and bleeding disorders, and certain cancers. In 2013, researchers studied the structure of one of these exchange factors, calle...
16 CitationsSource
#1Claudia Y. Janda (Stanford University)H-Index: 8
#2Luke T. Dang (UW: University of Washington)H-Index: 6
Last. K. Christopher GarciaH-Index: 97
view all 17 authors...
The authors describe water-soluble surrogate Wnt agonists, with specificity towards some frizzled (FZD) receptors, which can maintain human intestinal organoid cultures and have effects on the mouse liver in vivo.
115 CitationsSource
Cited By0
Newest