RT Journal Article
SR Electronic
T1 Filopodia-mediated basement membrane assembly at pre-invasive tumor boundaries
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.22.464987
DO 10.1101/2021.10.22.464987
A1 Emilia Peuhu
A1 Guillaume Jacquemet
A1 Colinda LGJ Scheele
A1 Aleksi Isomursu
A1 Ilkka Paatero
A1 Kerstin Thol
A1 Maria Georgiadou
A1 Camilo Guzmán
A1 Satu Koskinen
A1 Asta Laiho
A1 Laura L Elo
A1 Pia Boström
A1 Pauliina Hartiala
A1 Jacco van Rheenen
A1 Johanna Ivaska
YR 2022
UL http://biorxiv.org/content/early/2022/03/09/2021.10.22.464987.abstract
AB Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer, where the tumor is encapsulated by a basement membrane (BM). At the invasive phase, the BM barrier is compromised enabling tumor cells to escape into the surrounding stroma. The molecular mechanisms that establish and maintain an epithelial BM barrier in vivo are poorly understood. Myosin-X (MYO10) is a filopodia-inducing motor protein implicated in metastasis and poor clinical outcome in patients with invasive breast cancer (IBC). We compared MYO10 expression in patient-matched normal breast tissue and DCIS lesions and found elevated MYO10 expression in DCIS samples, suggesting that MYO10 might facilitate the transition from DCIS to IBC. Indeed, MYO10 promoted the formation of filopodia and cell invasion in vitro and positively regulated the dissemination of individual cancer cells from IBC lesions in vivo. However, MYO10-depleted DCIS xenografts were, unexpectedly, more invasive. In these xenografts, MYO10 depletion compromised BM formation around the lesions resulting in poorly defined tumor borders and increased cancer cell dispersal into the surrounding stroma. Moreover, MYO10-depleted tumors showed increased EMT-marker-positive cells, specifically at the tumor periphery. We also observed cancer spheroids undergoing rotational motion and recruiting BM components in a filopodia-dependent manner to generate a near-continuous extracellular matrix boundary. Taken together, our data identify a protective role for MYO10 in early-stage breast cancer, where MYO10-dependent tumor cell protrusions support BM assembly at the tumor-stroma interface to limit cancer progression, and a pro-invasive role that facilitates cancer cell dissemination at later stages.Highlights- Filopodia sculpt the tumor-proximal stroma in pre-invasive ductal carcinoma in situ (DCIS).- Filopodia-dependent basement membrane (BM) assembly limits invasive transition of DCIS-like tumors in vivo.- Loss of MYO10-dependent filopodia impairs BM assembly and induces an EMT-like phenotype at the tumor-stroma interface in vivo.- MYO10 filopodia are anti-invasive in DCIS but facilitate dissemination in invasive breast cancer.Competing Interest StatementThe authors have declared no competing interest.