Science - USA (2022-04-15)

preventing the growth of malignant clones
within them must also be a priority. In this
work, we show a mechanism for tumor elim-
ination that arises from an intrinsic prop-
erty of the epithelial barrier: its ability to
compartmentalize a luminal environment
segregated from the external milieu.Drosophila
TNF circulates systemically and bathes basal

organ surfaces but is latent because of TNFR’s

strict apical localization. However, when neo-

plastic cells arise, their altered polarity induces

basal localization of TNFR, where it binds

ligand and triggers apoptotic signaling. A

similar axis promotes wound healing; if the

epithelium is physically ruptured, ligand can

meet receptor and contribute to a pro-healing

JNK signaling program. Thus, a common molec-

ular mechanism inherent to epithelial geometry—

a mechanism that recognizes polarity changes

as a damage-associated molecular pattern

(DAMP) ( 21 )—underlies both homeostatic

programs (Fig. 4M). The function of the

TNF-TNFR system described here as an in vivo

sensor of epithelial integrity raises the possibility

300 15 APRIL 2022•VOL 376 ISSUE 6590 science.orgSCIENCE

EgrV Grnd

ptcts > dlg KD ptcts > grnd O/E

dlg KD

ptcts > dlg KD tak1 KD Wounded

A B

CD

EgrV Grnd DAPI EgrV Grnd DAPI

EgrV Grnd DAPI

E

DAPIEgrV

scrib -/- FB> egr KD

scrib -/-

G H

I J K L

***

n.s.

n.s.

n.s.

n.s.

***

***

n.s.

n.s.

FB> egr KD

scrib -/-

*

*

DAPIAP-1-RFP

DAPIDCP-1

***

n.s.

n.s. n.s.

DAPIDCP-1

• 
  

scrib -/-

DAPIAP-1-RFP

F

scrib -/-

AP-1-RFP

fluorescence (mean)

DCP-1

fluorescence (mean)

ctrl

scrib

-/-

FB> egr KD scrib

-/-

0

5

10

15

Volume (x10

6

m

3 )

WT Polarity loss Wounding

Egr

Grnd

JJNK JJNKK

M

JJNKK

Circulation

Lumen

Fig. 4. Mispolarization of Grnd permits Egr binding and cell elimination.
(AtoD)X-Zsections as in Fig. 3.dlg-depleted cells mislocalize Grnd baso-
laterally (A), evident especially when Grnd is overexpressed (B). EgrV binds
basally todlg-depleted cells. Codepletion ofdlgandtak1blocks cell elimination
but polarity defects remain (C). Mispolarized Grnd binds EgrV at basal surface.
Wounded discs show altered Grnd localization and basal EgrV binding (D).
(EtoL)X-Ysections. Wing discs containing onlyscribmutant cells bind Egr

preferentially at periphery (E). JNK signaling is increased in periphery compared

with core (F) and is dependent on circulating Egr (G). Quantitation is shown in

(H).scribdiscs grow larger when circulating Egr is depleted (I), and peripheral

apoptosis [(J), DCP-1] is reduced (K). Asterisks indicate DCP-1+cells in core.

Quantitation is shown in (L). (M) Model for role of polarized segregation

of TNF ligand and receptor in epithelial homeostasis. Scale bar, (A) 10mm; (E)

50 mm; (F) and (J) 100mm.

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